Tamm-Horsfali protein(THP) is urine's most abundant protein. Its function has remained unclear, despite extensive research for over a century. One of the hypotheses about its function has been that it acts as a host defense actor against urinary tract infection. We are one of two groups to createthe first gene knockout mousefor THP. n PRELIMINARY STUDIES, THP-deficient mice have difficulty clearing bacteria from the urinary bladder. The SPECIFIC AIMS of this proposalare: A1M#1) To define and circumscribe the role of THP as a host defensefactor against UTI a) To determine if THP (-/-) mice are more proneto cystitis (inflammation of urinary bladder) in comparison with THP (+/+) mice, after transurethralinoculation of E.coli. b) To determine if THP (-/-) mice are more prone to pyelonephritis (inflammation of kidneys) in comparison with THP (+/+) mice, after transurethral inoculation of E.coli. c) To determine if the severity of bladder and kidney infection in THP (-/-) mice is related to the specific type of fimbrial expression in E. coll. ', d) To determine if THP (-/-) mice are more prone to UTI with bacteria other than E co//r specifically Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus saprophyticus, Enterococcus fecaelis and Morganella morganii, as measured by bladder and kidney bacterial loads after transurethral inoculation. AIM#2) To determine the mechanism of THP affecting the susceptibility for UTI a) Effect of THP on bacterial clearance from bladder . b) Effect of THPon bacterial - urothelial cell interaction c) Effectof THP on bacterial-leukocyte interaction SIGNIFICANCE: These studies will clarify the function of urine's most abundant protein and will providenew knowledge about a host defense mechanism against UTI. The findings will allow a better understanding of the pathogenesis of UTI, a commonhuman illness.